In 1994 MacNicol had a prominent role as Alan Birch for the first season and under half of the second season of Chicago Hope before departing to take on a role on another TV series, Ally McBeal, also created by Chicago Hope's creator, David E. Kelley. However, he did return for one final guest appearance in episode five of the former show's fifth season.

MacNicol is known by television viewers for his Ally McBeal performance as eccentric attorney John Cage, for which he won an Emmy Award for Outstanding Supporting Actor in a Comedy Series in 2001. He also starred in the drama Numbers as physicist Dr. Larry Fleinhardt, and had a role as Tom Lennox in the sixth season of the hit FOX show 24. MacNicol reprised his role as Lennox in the film 24: Redemption. He also played a hotel receptionist in one episode of Cheers titled "Look Before You Sleep".

MacNicol was nominated for an Emmy for outstanding guest actor in the fifth season of Veep; however, this was rescinded after he appeared for all of ten seconds in a fifth episode of the season's ten episode run, hence disqualifying him as a part-time "guest" and joining him in the ranks of Dennis Miller and Henry Winkler whose nominations were also revoked.[6]